The present invention relates to novel 5-(2,3-dihydro-1H-pyrrolizin-5-oyl)-, 5-(2,3-dihydro-1H-pyrrolo[2,1-b]thia zol-5-oyl)-, 5-(2,3-dihydro-1H-pyrrolo[2,1-b]imidazol-5-oyl)-, and 5-(2,3-dihydro-1H-pyrrolo[2,1-b]oxazol-5-oyl)- derivatives of substituted 2,3-dihydro-1H-pyrrolizine-1-alkanoic or carboxylic acids and their corresponding salts, esters, nitriles, amides and substituted amides. These compounds are found to exhibit analgesic/anti-inflammatory activities with low ulcerogenic irritation and are effective inhibitors of platelet aggregation. For a chronic disease, for example, arthritis, it is crucial that the anti-inflammatory/analgesic agent be administered routinely and regularly at an effective dosage level without causing gastric irritation or ulcers.
Accordingly, it is an object of the present invention
(1) to provide novel nonsteroidal antiinflammatory and analgesic agents of lower ulcerogenic side effect; PA0 (2) to develop processes for the preparation of the novel compounds; PA0 (3) to provide methods of application of the novel compounds in the treatment of inflammatory diseases; and PA0 (4) to provide pharmaceutical compositions and formulations for the administration of these novel compounds. PA0 m is 0 to 2; PA0 q is 0 to 6; PA0 R.sup.2 Z can be at any available ring positions and Rhu 2 is R as previously defined; PA0 n is 0 to 2; PA0 R.sup.3 is PA0 X is --O--, --S--, --SO--, --SO.sub.2 --, --NR.sup.4 -- or --CHR.sup.4 --; PA0 Y is --O--, --S--, --SO--, --SO.sub.2 --, CHR.sup.4 -- or hydrogen providing that when Y is hydrogen, R does not exist; PA0 Z is --O--, --S--, --SO--, --SO.sub.2 --, --NR.sup.4, --CHR.sup.4 or halo especially fluoro, chloro or bromo providing that when Z is halo, R.sup.2 does not exist; and PA0 R.sup.4 is hydrogen or C.sub.1-6 alkyl as previously defined. PA0 R is PA0 m is 0 or 1; PA0 R.sup.2 Z is as defined above; PA0 q is 0 to 2; PA0 n is 0 or 1; PA0 R.sup.3 is hydroxy, C.sub.1-6 alkoxy, or lower(alkanoylaminoalkoxy), especially C.sub.1-6 alkanoylaminoalkoxy such as acetamidoethoxy; PA0 X is --S--, --SO-- or --CHR.sup.4 --; PA0 R.sup.4 is hydrogen or methyl; PA0 Y is --O--, --S--, --CH.sub.2 --, or H when R is absent; and PA0 Z is --S--, --CH.sub.2 --, or halo when R.sup.2 is absent. PA0 R is absent or C.sub.1-3 alkyl especially methyl; PA0 m is 0 or 1; PA0 q is 0 or 1; PA0 R.sup.2 Z is as defined previously; PA0 n is 0 or 1; PA0 R.sup.3 is hydroxy, C.sub.1-6 alkoxy or acetamidoethoxy; PA0 X is --S--, --SO--, or --CHR.sup.4 --; PA0 Y is oxygen, CH.sub.2 --, or H with the proviso that when Y is H, R is absent; PA0 Z is --S--, --CH.sub.2 --, or halo with the proviso that when Z is halo, R.sup.2 is absent; and PA0 R.sup.4 is hydrogen or methyl. PA0 (a) 5-(2,3-Dihydro-1H-pyrrolizin-5-oyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-1- carboxylic acid. PA0 (b) 5-(2,3-dihydropyrrolo[2,1-b]thiazol-5-oyl)-6-methyl-2,3-dihydro-1H-pyrroli zine-1-carboxylic acid. PA0 (c) Ethyl 5-(2,3-dihydro-1H-pyrrolo[2,1-b]imidazol-5-oyl)-6-methyl-2,3-dihydro-1H-py rrolizine-1-carboxylate. PA0 (d) Ethyl 5(2,3-dihydro-1-methyl-1H-pyrrolizin-5-oyl)-6-methyl-2,3-dihydro-1H-pyrrol izine-1-carboxylate. PA0 (e) Ethyl 5-(2,3-dihydropyrrolo[2,1-b]thiazol-5-oyl)-6-methyl-2,3-dihydro-1H-pyrroli zine-1-carboxylate-S-oxide. PA0 (f) Ethyl 5-(2,3-dihydro-1H-pyrrolizone-5-oyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-1 -acetate. PA0 (g) 5-(2,3-Dihydro-1-methyl-1H-pyrrolizin-5-oyl)-6-methyl-2,3-dihydro-1H-pyrro lizine-1-carboxylic acid. PA0 (1) water; PA0 (2) C.sub.1-20 alkanol especially methanol, ethanol, isopropanol and t-butyl alcohol; PA0 (3) lower ketone , e.g., acetone and methylethylketone; PA0 (4) lower ether including diethylether, 1,2-dimethoxyethane, tetrahydrofuran (THF), dioxane and diglyme; PA0 (5) a mixture of at least two of the solvents described in (1) to (4). PA0 Tri-(loweralkyl)amine, e.g., triethylamine PA0 pyrrolidine PA0 pyridine PA0 collidine PA0 ethanolamine PA0 quinoline, etc. PA0 Acetic acid PA0 Chloroacetic acid PA0 Chlorodifluoroacetic acid PA0 Dichloroacetic acid PA0 Difluoroacetic acid PA0 Trifluoroacetic acid PA0 Trichloroacetic acid PA0 Pentafluoropropanoic acid. PA0 Toluene PA0 Benzene PA0 Xylene PA0 Tetrahydrofuran PA0 1,2-Dimethoxyethane PA0 Dioxane PA0 Methylene chloride PA0 Acetic Acid PA0 (1) A compound of Formula (I) is treated with a lower alkanol or phenol in the presence of an acid such as sulfuric acid, hydrochloric acid, boron trifluoride or the like. PA0 (2) A compound of Formula (I) is converted to an acid halide such as acid chloride or bromide via treatment with a halogenating agent such as thionyl chloride or phosphorus pentachloride, followed by reaction with an alcohol or a phenol. PA0 (3) A compound of Formula (I) is treated with an alcohol in the presence of a condensing agent such as N,N'-dicyclohexyl-carbodiimide or the like.